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    The EU Clinical Trials Register currently displays   36379   clinical trials with a EudraCT protocol, of which   5993   are clinical trials conducted with subjects less than 18 years old.
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    EudraCT Number:2011-001564-21
    Sponsor's Protocol Code Number:GN09CP301
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-08-01
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2011-001564-21
    A.3Full title of the trial
    Towards Onset Prevention of COGnitive decline in adults with Down syndrome (the TOP-COG study)
    A.3.2Name or abbreviated title of the trial where available
    The TOP-COG study
    A.4.1Sponsor's protocol code numberGN09CP301
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNHS Greater Glasgow and Clyde
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    B.Sponsor: 2
    B.1.1Name of SponsorUniversity of Glasgow
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Information not present in EudraCT
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameSimvastatin
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSimvastatin
    D.3.9.1CAS number 79902-63-9
    D.3.9.2Current sponsor codeNot applicable
    D.3.9.3Other descriptive nameNot applicable
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Alzheimer's disease
    Down syndrome
    E.1.1.1Medical condition in easily understood language
    Alzheimer's disease
    Down syndrome
    E.1.1.2Therapeutic area Psychiatry and Psychology [F] - Mental Disorders [F03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level LLT
    E.1.2Classification code 10001896
    E.1.2Term Alzheimer's disease
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level LLT
    E.1.2Classification code 10013616
    E.1.2Term Down's syndrome
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The aims of the study are to gather the data needed to design a full-scale multi-centred RCT of oral simvastatin 40mg a day.

    The principal research questions are:

    What are the:
    (1) trial recruitment/retention rates and recruitment sources,
    (2) rates of tolerability/safety of oral simvastatin 40mg a day,
    (3) most sensitive instruments to detect early cognitive decline in adults with Down syndrome, and
    (4) perceptions of adults with Down syndrome and their carers on deciding whether to participate, on randomisation, and their experience of the assessments?
    E.2.2Secondary objectives of the trial
    The secondary reserach questions are:

    (5) what are the distributions of the primary (cognitive decline) and key secondary (adative behavior, general health/quality of life, service use, carer strain) outcome measures that would be used in a definitive RCT, and what are the sample size implications of these distributions,
    (6) is Aβ42/Aβ40 a biomarker for cognitive decline, and
    (7) do the results support proceeding to a full RCT?
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Qualitative sub-study "Your views count", included in the main protocol version 2, dated 26.6.11.
    E.3Principal inclusion criteria
    (1) Down syndrome.
    (2) Aged ≥50.
    E.4Principal exclusion criteria
    (1) No consent obtained.
    (2) Unable to comply with the protocol, including providing blood or saliva for baseline APO E e4 measurement, and venous or capillary blood for cholesterol measurement.
    (3) Dementia at baseline (as the study is investigating primary prevention).
    (4) Diabetes (as this is an indication for a prescription of a statin).
    (5) Clinically evident atherosclerotic disease (as this is an indication for a prescription of a statin).
    (6) Being at risk for cardiovascular disease (as this is an indication for a prescription of a statin).
    (7) Liver disease.
    (8) Chronic renal insufficiency.
    (9) Being prescribed:
    a) statin,
    b) fibrates,
    c) nicotinic acid,
    d) cyclosporine,
    e) azole antifungal,
    f) itraconazole,
    g) ketoconazole,
    h) macrolide antibiotics,
    i) erythromycin,
    j) clarithromycin,
    k) fusidic acid,
    l) HIV protease inhibitors,
    m) nefazodone,
    n) verapamil,
    o) amiodarone,
    p) warfarin.
    (10) Having previously had a statin serious adverse reaction.
    (11) Unable or unwilling to avoid consumption of grapefruit juice.
    (12) Excessive alcohol use (>21 units/week for men, or >14 units/week for women).
    E.5 End points
    E.5.1Primary end point(s)
    1: Feasibility
    (1) The numbers screened and recruited each month over the 6 month recruitment period.
    (2) The retention of participants in the study after 12 months.
    (3) The percentage of the total recruited from each source, and the number of contacts with each source to achieve this. The source will be identified at the initial telephone call to assess suitability to invite the person to participate. The number of contacts will be identified through the researcher and the SPCRN recording each one on a contact recording sheet.
    (4) The number recruited per base general population size. Base population size is that for Greater Glasgow and Clyde, Lothian, and Tayside Health Board area, according to Scottish government data.

    2: Tolerability and safety
    (1) Compliance will be assessed by counting returned tablets every 3 months.
    (2) Blood will be taken to measure muscle enzyme levels 6-12 weeks after starting the simvastatin/placebo.
    (3) 3 monthly interviews will be conducted using the AE schedule, in addition to recording spontaneously reported AEs using the standard sponsor’s AE protocol.

    3: Identification of the most suitable cognitive measures
    (1) Based on published data of measures of cognitive decline in Down Syndrome, we have identified eight tests considered most likely to be sensitive to change. The tests are in the domains of memory, attention and executive functioning. Scores at baseline and after 12 months of simvastatin/placebo will be compared for each of these measures to identify which show the greatest degree of change over the period, and have the greatest utility across the full range of intellectual disabilities (i.e. the tests that are completed by the highest number of participants). This will determine the primary outcome measure for the full-scale study.

    4: Participant/carer perceptions
    (1) Key themes will be identified from the semi-structured interviews to improve our understanding of participants' perspectives about research participation, randomisation and the experience of having the assessments.
    E.5.1.1Timepoint(s) of evaluation of this end point
    3, 6 and 12 months
    E.5.2Secondary end point(s)
    1: Effect size after 12 months simvastatin/placebo
    (1) cognitive decline
    (2) skill decline
    (3) general health/quality of life
    (4) service use and social changes

    2: Biomarkers
    (1) Abeta40/Abeta42
    E.5.2.1Timepoint(s) of evaluation of this end point
    12 months
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Each participant completes at the end of the 12 month assessment for all outcomes, except safety, for which completion is 30 days after the last dose of simvastatin/ placebo.
    The trial itself ends 24 months after it starts which will be 2 months after the final assessment, allowing time for analyses and dissemination.
    The entire study would be stopped prematurely if the ChI/sponsor interpreted advice from the independent DMEC to show detrimental effects on cognition, death, or SUSARs
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F. of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F. of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F. of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F. of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F. of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F. of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 65
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients No
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F. of subjects incapable of giving consent
    Adults with Down syndrome aged 50 and over
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state70
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    This is a pilot/feasibility study, and a full-scale RCT is needed before decisions would be likely to be taken regarding whether long term use of simvastatin was advisable. Should this subsequently be established as a recommended preventative intervention for all adults with Down syndrome, the intervention would be very inexpensive to implement (simvastatin costs 38p per 28 tablets).
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-09-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-07-05
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-09-14
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